KR19990082254A - Traniste-containing external preparation and its manufacturing method - Google Patents

Abstract

The present invention is a traniest external preparation having excellent release properties of the active ingredient, high skin absorption, sufficient concentration of an effective drug in skin tissue, and low skin irritation. The external preparation is an external preparation of an aqueous base containing a tranist, a salt thereof, or a mixture thereof as an active ingredient, and the aqueous base is a solvent, a dispersing agent, an absorption aid, a pressure-sensitive adhesive and / or a molding agent, and water of the tranist. The active ingredient is dissolved in the dissolving agent and dispersed in the aqueous base by the dispersing agent.

Description

Traniste-containing external preparation and its manufacturing method

The anti-allergic drug, tranist, is marketed as a drug for allergic diseases, and has been reported to show excellent efficacy against keloids and thickening scars [Kiyoshi Ichikawa et al., Oyo Yakuri (Pharmacometrics) 43 (5), 401 ( 1992); Haruo Suzawa et al., Nichi Yakuri-shi (Folio Pharmacol Japan) 99, 231 (1992). Tranyst is used as a formulation for capsules, tablets, dry syrups, fine granules and the like.

However, orally administered drugs are absorbed by the digestive tract, enter the liver through the portal vein, and are metabolized to show a so-called first pass effect. Thereafter, some of the drug is sent to the local site, so its bioavailability is lowered. Therefore, in order to maintain an effective blood drug concentration, a relatively large amount of drugs must be administered, so the expression of side effects increases. Furthermore, in order to treat keloids, thickening scars and allergic dermatitis, it is necessary to maintain an effective amount of the drug in the skin. Therefore, an external preparation, especially an external patch applied directly to the skin area is most preferable for the treatment of these diseases. It was thought.

Topical patch is a transdermal drug delivery system (TDS) of drugs, attracting attention as a topical formulation as well as a new method of administration of systemic drugs. That is, drugs absorbed through the skin epidermis from the formulation are incorporated into the bloodstream via subcutaneous capillaries in TDS, whereas some of the drug is delivered directly to the topical area of the subcutaneous tissue without mixing into the bloodstream. For the purpose of this topical effect, many external patch using non-steroidal anti-inflammatory drug systems (NSAIDS) has already been developed and marketed.

In addition, transdermal administration by external patch is effective as a controlled release method of drug that can continue the action of the drug, and because it can control the blood concentration of the drug, Expression can be suppressed.

However, the skin has the property of preventing foreign bodies from invading the body from the outside. In order to increase the skin absorption of the drug is sometimes used as a base, a keratin dissolving agent such as Azone, the keratin solubility is high skin irritation, there is a fear of causing side effects such as rash. In addition, since the skin absorbency of the drug also depends on the properties of the molecule, the formulation for effectively transdermal absorption of the drug is extremely limited.

Moreover, tranist is extremely poorly soluble in water and difficult to dissolve in methanol, ethanol and ethyl acetate in organic solvents, while soluble in dimethyl formamide, pyridine, dioxane and acetone, but these solvents are not suitable as bases for external preparations. not. And some types of fatty acids and their esters, animal and vegetable fats, terpene compounds and alcohols can dissolve the drug to some extent, but the solubility is not enough, the drug is not well dispersed in the prepared formulation.

Since this also affects the transdermal absorption of the drug, the solubility of the tranist makes it difficult to formulate as an external patch.

As external preparations containing tranist, a tranist-containing external patch for improving skin absorption by containing certain kinds of fatty acid esters and alcohols as an absorption aid has been developed (Japanese Patent Laid-Open No. 4-99719). ). However, since this external patch requires a large amount of an absorption aid such as fatty acid ester or alcohol, it may cause skin irritation.

In addition, a trianist-containing ointment composition containing a basic aqueous solution as an absorption aid has also been developed (Japanese Patent Laid-Open No. Hei 6-128153). Since this external preparation contains a basic aqueous solution as an absorption aid, its pH is basic. In addition, since the basic substance itself may cause skin irritation, there is a problem that it is difficult to actually use this preparation.

The present invention relates to an external preparation containing tranilast as an active ingredient, and more particularly, the skin absorption of the active ingredient in the preparation is good by improving the base, and in the skin tissue after application Nodule, including keloids, hypertrophic scars, psoriasis, palmoplantar pustulosis, and urticaria perstans Prurigo nodularis, allergic dermatitis (e.g., atopic dermatitis, contact dermatitis, skin pruritus, stinging of insects, acute strofilus, etc.) and progressive scleroderma keratosis And topical application for the purpose of treatment of lichen simplex chronicus and other eczema and dermatitis groups.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is an explanatory diagram of a permeation / diffusion cell used for a skin penetration rate test of a drug of the formulation of the present invention.

An object of the present invention is to solve the above-mentioned problems of the prior art in order to achieve the practical use of the external preparation with a triniast as an active ingredient, the skin absorption of the active ingredient in the formulation is good and the effective concentration of the drug in the skin tissue To maintain a sufficient and less skin irritation to provide a tranist containing external preparation.

As reported earlier [Toyomi Waseda, The Japanese Journal of Dermatology, 99 (11), 1159 (1989)], the effective concentration of traniest in tissues for the treatment of keloid patients is a 300 mg dose three times a day. Dividing is reported at about 8-10 μg / g in oral administration for 3 days. And another report [Yasuo Goto et al., Kiso Rinsho (The Clinical Report), 25 (15), 69 (1991)], 50, 100 and 200 mg / kg in experiments using a rat carrageenan-induced granulation tissue model. Dose-dependent inhibitory effect was given by oral administration of the tranist of 14 days, and the concentrations of drugs in the skin tissue after 1 hour of final administration were 4.2 ± 0.4, 10.3 ± 0.9, and 23.17 ± 1.7㎍ / g, respectively. Reported. Therefore, even in external preparations, the concentration of the tranist in the skin tissue after application of the skin is preferably equal to or above the above values.

Keloids, hypertrophic scars and allergic dermatitis are diseases of any kind on the surface of the skin, and not only have an ugly appearance but also have strong itching or pain as subjective symptoms. Therefore, it is preferable that the external preparation applied directly to the affected part does not cause irritation by contact with the affected part and the base in the preparation does not cause skin irritation. In particular, it is preferable that the patch be freely stretched, not too strong in adhesion, and less resistant at peeling. From this point, a water-blended puff agent is preferable, and if it is a plaster agent, it can be prepared as a soft patch.

The present invention provides an external preparation for achieving the above object and a method for producing the same, an external preparation made of an aqueous base containing a tranist, a salt thereof, or a mixture thereof as an active ingredient, wherein the aqueous base is a solvent, A transnitrative-containing external preparation containing a dispersant, an absorption aid, a pressure-sensitive adhesive and / or a prosthetic agent, and water, and the active ingredient is dissolved in a dissolving agent and dispersed in an aqueous base by the dispersing agent, and coated on a support. It is to provide the external patch made.

Furthermore, the present invention dissolves an active ingredient selected from a tranist, a salt thereof, or a mixture thereof in a dissolving agent, and adds a dispersing agent to the solution to prepare an aqueous solution containing an absorption aid, an adhesive and / or a prosthetic agent, and water and It also relates to a process for producing a tranist-containing external preparation characterized by mixing, and a method for producing an external patch obtained by applying the external preparation on a support.

The tranilast as an active ingredient of the external preparation of the present invention is N- (3,4-dimethoxycinnamoyl) -anthranilic acid and its salt represented by the following formula.

As for content of the tranist in a formulation, 0.05-5 weight% is preferable. If the content of the active ingredient is too small, the pharmacological action is insufficient, and if too much, no additional benefit is shown, so it is economically disadvantageous.

In the external preparations of the present invention, the solubilizing agent of tranist is an oily substance consisting of fatty acids and derivatives thereof, animal and vegetable fats and oils, terpene compounds, alcohols, crotamitone, N-methyl-2-pyrrolidone and triethanolamine. Selected from the components.

Fatty acids and derivatives thereof used as solubilizers are monocarboxylic acids having 3 to 30 carbon atoms or esters thereof. Examples of fatty acids include octadecanoic acid, oleic acid and linoleic acid, and fatty acid esters include glycerol monocaprate, tetradecyl tetradecanoate, hexadecyl hexadecanoate, oleyl oleate and isopropyl myristate. In addition, examples of the fatty acid alkali metal salts include fatty acid sodium salts.

Animal and vegetable oils include almond oil, olive oil, camellia oil, fermented oil, peppermint oil, soybean oil, sesame oil, mink oil, cottonseed oil, corn oil, soybean oil, palm oil, eucalyptus oil, castor oil, hardened castor oil, and soy lecithin. Can be mentioned. Examples of the terpene compound include menthol, menton, limonene, pinene, piperidone, terpinene, terpinolene, terpinol, carbenol, and the like. Examples of the allools include non-aqueous alcohols such as benzyl alcohol and octanol.

Furthermore, examples of organic solvents other than those listed above that can be used as the solubilizer include crotamiton, N-methyl-2-pyrrolidone, triethanolamine, and the like.

Preferred examples of the above oily components include oleic acid, linoleic acid, glycerol monocaprate, oleyl oleate, castor oil, hardened castor oil, soybean oil, soybean lecithin, 1-menthol, mentone, limonene, benzyl alcohol, crotami Tones, N-methyl-2-pyrrolidone and triethanolamine, and especially crotamiton and N-methyl-2-pyrrolidone are most preferred because they not only dissolve the tranist but also improve skin absorption. . These solubilizers may be used independently or may be used in combination of 2 or more type. As for the total compounding quantity, 2-5 weight% is preferable.

When preparing the external preparation, when the solution obtained by dissolving the tranist in the dissolving agent is mixed with the absorption aid, the pressure-sensitive adhesive and / or the retaining agent and the aqueous base containing water, the tranist should be uniformly dispersed in the final formulation. Tranist is extremely poorly soluble in water as described above, and therefore, when mixed with an aqueous base, a part thereof does not dissolve, so that dispersibility is poor. If the drug is not sufficiently dispersed in the formulation, its release is reduced, resulting in a decrease in skin absorption.

According to the present invention, a dispersant is dissolved in a dissolving agent, and a dispersant is added thereto and mixed well so that at least a part of the tranisest, preferably substantially all of the tranisest, is supported by the dispersant and then mixed with an aqueous base. Formulations with good acidity can be prepared. The dispersant that can be used is a pharmaceutically acceptable solid powder, in particular an inorganic solid powder, which has the ability to carry the tranist dissolved in the dissolving agent. Examples of preferred dispersants include silicon dioxides such as hydrous silicon dioxide or hard anhydrous silicon, and silicates such as hydrous magnesium sulfate or hydrous aluminum silicate, with hydrous silicon dioxide (white carbon) being most preferred.

That is, a formulation having good dispersibility can be prepared by dissolving the tranist in a dissolving agent, adding white carbon to the solution, mixing the mixture sufficiently, adsorbing and supporting the tranist, and mixing with an aqueous base.

The ratio of the amount of the dispersant to the total amount of the tranist and the dissolving agent is 1/3 to 1/5.

Absorption aids that promote the absorption of tranist from the preparation into the skin tissue include fatty acids and derivatives thereof used as bases for external preparations, animal and vegetable fats and oils, terpene compounds, alcohols, crotamiton and N-methyl-2-pyrroli. It is chosen from money. Preferred examples include oleic acid, 1-menthol, ethanol, propylene glycol, butanediol, 1,2,6-hexanetriol, benzyl alcohol, crotamiton and N-methyl-2-pyrrolidone, and the like. Or you may use in combination of 2 or more type. Among them, propylene glycol, butanediol or N-methyl-2-pyrrolidone is most preferred. These compounds may be added in a compounding amount of 0.5 to 10% by weight with respect to the formulation, but since the compounding amount of 2 to 5% by weight can ensure sufficient drug concentration in the skin tissue after application, and furthermore, it does not cause skin irritation. desirable.

pH value is another factor that promotes the absorption of tranist into skin tissue. Tranyst is excellent in skin absorption at pH in the range of neutral to weakly acidic region, but the pH range is preferably 3.5 to 7.5 in consideration of skin irritation and shape retention. Citric acid and tartaric acid can be used to adjust the pH of the formulation.

Since the formulation is affixed directly to the affected area exposed to the skin surface, the external patch should not cause contact irritation to the affected area, maintain the form of the formulation, and maintain sufficient adhesion. As a patch satisfying the above conditions, a non-aqueous soft type plaster may also be used, but an aqueous type is preferably used.

Water-soluble high molecular compounds used as pressure-sensitive adhesives and / or prosthetics include polyacrylic acid and its derivatives, acrylate copolymers and emulsions thereof, cellulose derivatives and their derivatives, gum arabic, gelatin, casein, polyvinyl alcohol, polyethylene glycol, polyvinyl Pyrrolidone, a methyl vinyl ether / maleic anhydride copolymer, its emulsion, and a natural polysaccharide can be mentioned, These compounds may be used individually or in combination of 2 or more types. The total compounding amount added to the formulation is 5 to 15% by weight. Among them, it is preferable to use polyacrylic acid and its derivatives or acrylate copolymers and emulsions thereof. When using sodium polyacrylate, activated alumina, synthetic aluminum silicate, aluminum hydroxide, etc. can be used as an aluminum compound which can carry out crosslinking reaction.

Examples of fat-soluble high molecular compounds that can be used as pressure-sensitive adhesives and prosthetics include natural rubber, isoprene rubber, polyisobutylene rubber, styrene-butadiene rubber, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block air Coalesce, silicone, rosin, polybutene, lanolin, waserine, plastibase, beeswax, solid paraffin and the like.

Examples of the polyhydric alcohol that can be used as an adhesive and / or a prosthetic agent include glycerol, polyethylene, glycol, ethylene glycol and D-sorbitol, and these may be used alone or in combination of two or more thereof. As for the total compounding quantity, 5-40 weight% is preferable.

The adhesives and / or prostheses described above can be used to provide a tranist containing topical patch that maintains tackiness, prosthesis, and flexibility for a long period of time and is less skin irritant.

Furthermore, non-ionic surfactants or ionic surfactants, other pharmaceutical additives such as polyacrylic acid metal salts, bentonite, titanium oxide and the like may be used as needed.

According to the present invention, the Traniras-containing external preparation prepared in this way is applied to a support such as a base cloth, for example, a flannel, a nonwoven fabric, and spread, and then polyethylene, polypropylene is applied to the exposed surface of the formulation facing the bubble. A film for peeling, such as polyester, can be affixed and can be used as a commercial item of an external preparation type.

And the external preparation of this invention can also be used as an ointment or cream agent which apply | coats directly to a affected part, without spreading especially on a support body and expanding.

In the tranist-containing external preparation of the present invention, the tranist, which is poorly soluble in water, is dissolved in a dissolving agent and dispersed in an aqueous base in a sieve supported on a dispersing agent, so that the tranist is uniformly dispersed in the aqueous base. Therefore, the active ingredient is easily released and excellent in skin absorption, it is possible to maintain a sufficiently high concentration of the effective drug in the skin tissue after affixation and less skin irritation.

The present invention is explained in more detail by the following examples, but the present invention is not limited to these examples.

Example 1

3 g of trianist was slowly dissolved in a mixed solution of 20 g of crotamiton and 10 g of ethanol at 60 to 70 ° C. After adding 7 g of white carbon thereto, the mixture was sufficiently mixed and ethanol was removed under reduced pressure. Subsequently, 5 g of 1-menthol and 2.5 g of titanium oxide were added thereto, and the mixture was mixed to prepare a tranist solution. Separately, 25 g of tartaric acid was dissolved in 552 ml of water, and then 50 g of sodium polyacrylate, 60 g of acrylic acid starch, and 250 g of glycerol were added, and the obtained mixture was sufficiently mixed to prepare an aqueous base liquid mixture.

The tranist solution, the aqueous base mixture solution, 0.5 g of dry aluminum hydroxide gel and 25 g of methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion were uniformly kneaded to obtain a 0.3% tranist-containing external preparation. The pH of this formulation was 5.2.

Example 2

3 g of trianist was dissolved in a mixed solution of 20 g crotamiton and 25 g N-methyl-2-pyrrolidone. After adding 7 g of white carbon thereto, the solution was sufficiently mixed and ethanol was removed under reduced pressure. Then 5 g of 1-menthol and 2.5 g of titanium oxide were added and mixed to prepare a tranist solution. Separately, 25 g of tartaric acid was dissolved in 527 ml of water, and then 50 g of sodium polyacrylate, 60 g of acrylic acid starch, and 250 g of glycerol were added, and the obtained mixture was sufficiently mixed to prepare an aqueous base liquid mixture.

The traniest solution, the aqueous base liquid mixture, 0.5 g of dry aluminum hydroxide gel and 25 g of methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion were uniformly kneaded to obtain a 0.3% tranist external preparation. The pH of this formulation was 5.2.

Example 3

Example 1 50 g of butanediol was added to an aqueous base liquid mixture in the same composition containing the base of the tranist and the external preparation described in Example 1, and glycerol was used in an amount of 200 g instead of 250 g, to prepare a 5% butanediol-containing traniest external preparation. Got it.

Example 4

Example 3 A 5% propylene glycol-containing tranist external preparation was obtained using propylene glycol instead of butanediol in the same composition containing the base of the tranist and external preparation described in Example 3.

Example 5

In the same composition containing the base for external preparation as described in Example 1, 10 g of tranist was used, and further, the pH was adjusted using an amount of tartaric acid and various sodium polyacrylates (50 g) as shown in the following table. 1% tranist external preparations were obtained, 4.3, 5.4, 6.3 and 7.4.

Tartaric acid (g) Sodium Polyacrylate [manufactured by Suwa Denki Co., Ltd. in Japan] pH Example 5-1 Example 5-2 Example 5-3 Example 5-4 5020100 Viscomate NP-700Biscomate NP-700Biscomate NP-600Biscomate F480SS 4.35.46.37.4

[Performance evaluation test]

Test Example 1

The effects of pH on the skin permeability of the drug using the formulations of Examples 5-1 to 5-4 were evaluated by in vitro experiments as permeation rate.

In this test, the permeation / diffusion cell shown in FIG. 1 was used.

The rat abdominal skin was inserted into the fastener 1, and the patch to which the agent to be tested was applied to the fastener 2 was spread on the support, and the external preparation was contacted with the rat abdominal skin of the fastener 1. And the container 3 was filled with 5.18 ml of Tyrode's solution so that air did not enter. The permeation / diffusion cell was placed in an incubator maintained at 37 ° C., and 0.5 ml of the tyrode solution 5 was collected at each time within 1 to 7 hours while stirring the tyrode liquid 5 with the stirrer 4, The permeation rate of the drug in the external preparation to be tested to the rat abdominal skin was determined by measuring the drug concentration therein. Drug amount was measured by HPLC method. The results are shown in Table 1.

HPLC conditions

Column: CAPCELLPAK C18 (SG120) 4.6mm × 150mm

Mobile phase: 50 mM ammonium acetate buffer (pH 6.0) / acetonitrile

= 750/250 (0-10.5 min)

375/625 (10.5-15 min)

750/250 (15-20 min)

Column temperature: 40 ℃

Flow rate: 1.0ml / min

Detection Wavelength: Trinast: 320nm

: Internal standard (ethyl p-hydroxybenzoate): 254nm

Holding time: Tranylast: 5min, Internal standard: 10min

Table 1: Effects of pH of external preparations on transdermal absorption of traniest

PH of base Permeation (μg / cm ² ) n = 31hr 3hr 5hr 7hr 24hr Penetration rate ^{* 1} (5 to 24 hr) 4.35.46.37.4 0.00 0.02 0.15 0.40 4.210.00 0.03 0.10 0.40 3.790.00 0.00 0.12 0.35 2.930.00 0.00 0.04 0.11 0.17 0.22 ± 0.020.20 ± 0.030.15 ± 0.030.06 ± 0.02

^* 1: μg / cm ² / hr ± SE

Test Example 2

In the same manner as in Experiments 3 and 4, preparations containing 2%, 5%, and 10% of propylene glycol and butanediol as absorption aids and 2.5% of N-methyl-2-pyrrolidone, respectively, were prepared. The skin absorption of propylene glycol, butanediol and N-methyl-2-pyrrolidone, which are skin absorption aids, was evaluated using the patch applied and spread on the support to evaluate the penetration rate of the tranist and the cumulative amount in the skin. . The results are shown in Table 2. The test of the skin penetration rate was carried out according to the method described in Test Example 1. Drug concentration in the skin was measured as described below.

Wistar-Imamichi male rats (200 g) were anesthetized with ether, and the hairs of the abdomen were cut out using a barber machine and a razor, and then a formulation (3 × 3 cm) was applied to the abdominal skin. After 8 hours of application, the rats were killed and the skin at the center of the application site was sufficiently removed by the strippimg with a cellophane tape to remove the stratum corneum, the fat and the capillaries on the dermis, and then the puncher. Punched with a punch (ø 1.0 cm) to extract and cut the dermis. The cut skin sections were then mixed with 2 ml of methanol, 1 ml of ethanol solution (10 μg / ml) of ethyl p-hydroxybenzoate (internal standard), and 0.5 ml of 50 mM ammonium acetate buffer (pH 6.0), and the resulting mixture was prepared in micro Homogenize by microhomogenization, centrifuged at 15,000 rpm for 5 minutes, and the supernatant used for HPLC. HPLC conditions were according to the method described in Test Example 1.

Table 2: Effect of Skin Absorption Formulation on the Skin Absorption of Tranist

Absorption aid Penetration rate (㎍ / cm ² / h) Drug concentration in skin (㎍ / g) -2% propylene glycol 5% propylene glycol 10% propylene glycol 2% butanediol 5% butanediol 10% butanediol 2.5% N-methyl-2-pyrrolidone 0.22 ± 0.010.38 ± 0.070.33 ± 0.070.68 ± 0.100.50 ± 0.130.64 ± 0.180.83 ± 0.070.68 ± 0.10 26.01 ± 1.2944.93 ± 4.6645.92 ± 8.7135.24 ± 0.6936.04 ± 5.0849.74 ± 7.1933.08 ± 0.9253.23 ± 10.88

As described above, the present invention is a tranist external preparation having excellent release properties of active ingredients, high skin absorption, sufficient concentration of effective drug in skin tissue, and low skin irritation. The external preparation is an external preparation of an aqueous base containing a tranist, a salt thereof, or a mixture thereof as an active ingredient, and the aqueous base is a solvent, a dispersing agent, an absorption aid, a pressure-sensitive adhesive and / or a molding agent, and water of the tranist. The active ingredient is dissolved in the dissolving agent and dispersed in the aqueous base by the dispersing agent.

The practical application of the traniest external preparation according to the present invention can solve various problems of the conventional external preparation of this type, and therefore, its industrial significance in this field is important.

Claims (13)

An external preparation of an aqueous base containing a tranist, a salt thereof, or a mixture thereof as an active ingredient, wherein the aqueous base contains a solvent, a dispersing agent, an absorption aid, a pressure-sensitive adhesive and / or a prosthetic agent, and water of the tranist. And the active ingredient is dissolved in the solubilizing agent and dispersed in an aqueous base by the dispersing agent. The externally-containing external preparation according to claim 1, wherein the active ingredient dissolved in the dissolving agent is supported in the dispersing agent and dispersed in an aqueous base. The oil solvent according to claim 1, wherein the solubilizer of the tranist is selected from fatty acids and derivatives thereof, animal and vegetable fats and oils, terpene compounds, alcohols, crotamiton, N-methyl-2-pyrrolidone and triethanolamine. External preparation as an ingredient. The tranist external preparation according to claim 3, wherein the dissolving agent is crotamitone. The tranist external preparation according to claim 3, wherein the solubilizer is N-methyl-2-pyrrolidone. The tranilast external preparation according to claim 1, wherein the disintegrating agent is silicon dioxide or silicate. The intrastrate external preparation according to claim 1, wherein the absorption aid is propylene glycol or butanediol. The external preparation for a tranist according to claim 1, wherein the pressure-sensitive adhesive and / or the prosthetic agent are selected from water-soluble polymer compounds, fat-soluble polymer compounds, and polyhydric alcohols. The external preparation for a tranist according to claim 1, wherein the pH of the preparation is in the range of 3.5 to 7.5. The external patch which apply | coats and spreads the traniest external preparation of any one of Claims 1-9 to a support body. The external preparation according to any one of claims 1 to 9, which is an ointment or a cream agent. After dissolving an active ingredient selected from a tranist, a salt thereof, or a mixture thereof in a solubilizer of a tranist, a dispersant is added, and the solution is mixed with an absorption aid, an adhesive, and / or an aqueous base containing a prosthetic agent and water. The manufacturing method of a tranist containing external preparation characterized by the above-mentioned. After dissolving an active ingredient selected from a tranist, a salt thereof, or a mixture thereof in a solubilizer of a tranist, a dispersant is added, and the solution is mixed with an absorption aid, an adhesive, and / or an aqueous base containing a prosthetic agent and water. A method of producing a tranist-containing external preparation, which is applied to a support and expanded.